Cellular Senescence in Prostate Cancer Reoccurrence

The induction of cellular senescence is often seen a beneficial therapeutic strategy for preventing the growth of cancer.  This may certainly be the case in the short-term, but the biological impact of senescent cells in the long-term is greatly understudied.  Senescent cells are more than just a permanent state of growth arrest; they also display an immune-evoking pro-inflammatory secretory phenotype.   However, for some yet unknown reason, senescent cells can evade immune clearance and potentially alter their microenvironment by continuously secreting of pro-inflammatory factors.  These pro-inflammatory factors are thus one possible mechanism by which senescent cells could promote the reoccurrence of cancer following senescence therapy.

Prostate cancer (PCa) is one of the most common cancers in American men and a leading cause of cancer- related death.  Initial PCa tumours are dependent upon the presence of androgen, such as testosterone, for growth.  As such, undergoing androgen deprivation therapy (ADT) is currently the most effective procedure for suppressing tumour progression. ADT not only causes tumour cell death leading to reduction in tumour size, but also induces a proliferative arrest in a large fraction of tumour cells.  Within a few years following ADT, the PCa can reemerge, that are no longer dependent on androgen for growth, and for which there are currently no effective therapeutic treatment strategies. Recurrence of nonresponsive or androgen-refractory tumours reduces patient life expectancy to less than two years. 

To investigate the mechanisms of PCa reoccurrence, Burton et al focused their efforts on the cells undergoing proliferative arrest in response to ADT.  They provide evidence that androgen deprivation-induced proliferative arrest is in fact cellular senescence, termed ADIS (androgen deprivation-induced senescence).  The induction of ADIS appears to be due to intracellular up-regulation of ROS and consequently DNA damage. Their data show that continuous exposure of an androgen-sensitive PCa cell line (LNCaP) to the senescent microenvironment, leads to the appearance of cells with androgen-independent characteristics.  Further, it is shown that pharmacologic enforcement of the p53-Bax pro-death pathway prior to androgen deprivation (AD) preferentially triggers cellular death rather than cellular senescence. It is thus postulated that the use of drug therapies prior/during ADT that promote cell death rather than cellular senescence may prevent/reduce androgen refractory PCa. 

The more difficult question to answer concerns the mechanisms that facilitate the appearance of cells with androgen-refractory characteristics.  One possibility is that the secretory phenotype of senescent cells stimulates the proliferation of so called, cancer stem cells (CSCs).  The senescent secretory profile is similar to that which occurs during a wound healing response, suggesting CSC may proliferate to facilitate wound repair but in this context facilitates tumour formation.  Interestingly, TAp63, a marker of basal prostatic cells, a progenitor population known to survive androgen ablation and is involved in the maintenance of adult stem cells is elevated in the emerging androgen-refractory cells. TAp63 overexpression has also been associated with resistance to premature senescence, suggesting the emerging androgen-refractory cells, at least in part, may be the result of selective pressure favoring the proliferation of cells resistant to ADIS.  Further, the secretory phenotype of the surrounding senescent cells may facilitate the expansion of ADIS resistant cells. 

This work is important because it addresses the controversial issue of whether AD-induced senescence in cancer cells promotes the progression of the disease; if this is the case, these phenomena can provide therapeutic targets to prevent progression.  Additionally, this study provides a method for generating and expanding androgen-refractory cells in a shorter period of time, cells which can be used for further study.  

Link to Article: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0068003

DOI: 10.1371/journal.pone.0068003 

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The main focus of ageing research is to prevent/combat age-related disease and disability, allowing everyone to live healthier lives for longer.